This invention relates to methods for selective synthesis of 4-substituted-pyrrole-2-carbaldehyde compounds, via alkylation reactions.
Pyrroles are a family of heterocyclic compounds comprising a five-membered ring residue with four carbon atoms, one nitrogen atom, and two carbon-carbon double bonds. A wide variety of substituent groups (designated generally herein as xe2x80x9cSxxe2x80x9d) may be bonded to any of the five atoms of the pyrrole ring. The permissible substituent groups include but are not limited to hydrogen, alkyl groups, aromatic groups, acyl groups, halides, etc . The present invention relates to methods for selectively converting certain pyrrole-2-carbaldehydes (i.e. pyrrole compounds having an aldehyde substituent at the 2-position of the pyrrole ring) to 4-alkylated-pyrrole-2-carbaldehyde compounds having alkyl residues or groups (xe2x80x9cR4xe2x80x9d) at the 4-position of the pyrrole ring, as shown below. 
wherein R4 is an alkyl or substituted alkyl substituent having at least four carbon atoms.
As disclosed by Streitweiser and Heathcock (Introduction to Organic Chemistry, Macmillan Publishing Co. Inc., New York, 1976, at pages 1080-1088) pyrrole rings may undergo electrophillic substitution reactions analogous to those typical of benzene-type aromatic compounds. For example, pyrroles undergo xe2x80x9cFriedel-Craftsxe2x80x9d type xe2x80x9calkylationxe2x80x9d reactions, in which an alkylating agent (such as an alkyl halide, an alcohol, or an olefin) is reacted with a pyrrole in the presence of a catalyst, which results the removal of a hydrogen from one of the pyrrole carbons, and substitution of an xe2x80x9calkylxe2x80x9d group or residue therefore.
Friedel-Crafts alkylation reactions have been utilized by prior workers to synthesize 4-substituted-pyrrole-2-carbaldehyde compounds. For example, Anderson et.al. (Can. J. Chem. 56, 654-657 (1978)) reacted pyrrole-2-carbonitrile with t-butyl chloride in the presence of aluminum or gallium chloride catalysts, to obtain either 4-t-butyl-pyrrole-2-carbonitrile, or 5-t-butyl-pyrrole-2-carbonitrile. Each of the two isomers of the t-butyl-pyrrole-2-carbonitriles were then reduced to the corresponding aldehydes. 
In another approach, Mueller-Westerhoff and Sweigers (Synthetic Communications, 24(10), 1389-1393 (1994)) protected the nitrogen atom of a pyrrole, alkylated in the 4-position with t-butyl chloride/aluminum chloride, deprotected the nitrogen atom, then formulated the 2-position utilizing a Vulsmeir reagent. 
In yet another approach to 4-alkyl-pyrrole-2- carbaldehydes, Anderson et.al.(Can. J. Chem., 44, 1831-1839 (1966)) disclosed selective isopropylation of pyrrole-2-carbaldehyde in the presence of various catalysts to give 4-isopropyl-pyrrole-2-carbaldehyde. 
Recently, three United States patent applications, including provisional patent application Serial No. 60/123,058, filed Mar. 5, 1999, provisional patent application Serial No. 60/123,962, filed Mar. 12, 1999, and U.S. utility patent application Ser. No. 09/518,863, filed Mar. 3, 2000 (which are hereby incorporated by reference in their entirety) disclose use for certain classes of 4-alkyl-substituted-pyrrole-2-carbaldehydes, i.e., as intermediates for the synthesis of certain porphyrin compounds.
The 4-alkyl-pyrrole-2-carbaldehydes provided by the current invention can also be used to synthesize various dipyrroles or tripyrroles, which can be intermediates for the synthesis of porphyrins having 4-alkyl substituents, according to the methods described in U.S. patent application Ser. No. 09/524,621, filed Mar. 13, 2000. Additionally, these classes of 4-alkyl-pyrrole-2-carbaldehydes and 4-alkyl-2-hydroxymethyl pyrroles may be valuable intermediates for the synthesis of pharmaceuticals containing heterocyclic residues.
Therefore, there is a need for improved methods and processes for synthesizing 4-alkyl-pyrrole-2- carbaldehydes including, and 4-tertiary-alkyl-pyrrole-2-carbaldehydes.
The present invention provides improved processes for synthesizing 4-alkyl-pyrrole-2-carbaldehydes, including 4-tertiary-alkyl-pyrrole-2-carbaldehydes. Therefore, this invention, in one aspect, relates to a process for making a 4-alkyl substituted pyrrole-2-carbaldehyde compound comprising reacting:
a. a pyrrole-2-carbaldehyde compound; and
b. an alkylating agent having at least four carbon atoms; in the presence of at least one catalyst; to form a 4-alkyl substituted pyrrole-2-carbaldehyde compound.
The invention further provides a process for making 4-t-butyl-pyrrole-2-carbaldehyde compound comprising:
a. dispersing pyrrole-2-carbaldehyde and from about 1.0 to about 1.5 molar equivalents of AlCl3 in a solvent:
b. adding from about 0.8 to about 1.3 molar equivalents of a t-butyl-halide compound to the dispersion, and
c. reacting the dispersion to form 4-t-butylpyrrole-2-carbaldehyde.
In yet another aspect, the instant invention provides a process for making a 4-tertiary-alkyl substituted pyrrole-2-carbaldehyde compound comprising:
a. reacting a pyrrole and a Vilsmeir reagent to produce a 2-substituted pyrrole compound; and
b. further reacting the 2-substituted pyrrole compound with an alkylating agent, in the presence of a catalyst; to form the 4-tertiary-alkyl substituted pyrrole-2-carbaldehyde compound.
Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the Examples included therein and to the Figures and their previous and following description.
Before the present compounds, compositions and methods are disclosed and described, it is to be understood that this invention is not limited to specific synthetic methods, specific pharmaceutical carriers, or to particular pharmaceutical formulations or administration regimens, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
It must be noted that, as used in the specification and the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9canxe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to xe2x80x9can aromatic compoundxe2x80x9d includes mixtures of aromatic compounds, reference to xe2x80x9ca pharmaceutical carrierxe2x80x9d includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from xe2x80x9caboutxe2x80x9d one particular value, and/or to xe2x80x9caboutxe2x80x9d another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent xe2x80x9cabout,xe2x80x9d it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:
References in the specification and concluding claims to parts by weight, of a particular element or component in a composition or article, denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
A weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.
A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more xe2x80x94OCH2CH2Oxe2x80x94 units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more xe2x80x94CO(CH2)8COxe2x80x94 moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
The term xe2x80x9calkylxe2x80x9d as used herein refers to a saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. Preferred alkyl groups herein contain from 4 to 18 carbon atoms. The term xe2x80x9clower alkylxe2x80x9d intends an alkyl group of from one to six carbon atoms, preferably from one to four carbon atoms. The term xe2x80x9ccycloalkylxe2x80x9d intends a cyclic alkyl group of from three to eight, preferably five or six carbon atoms. The term xe2x80x9csubstituted alkylxe2x80x9d as used herein refers to an alkyl group having one or more aromatic, heteroaromatic, or heteroatomic atoms or residues bonded thereto.
The term xe2x80x9carylxe2x80x9d denotes an aromatic ring radical containing 6 to 18 carbons that includes phenyl and naphthyl. The term xe2x80x9csubstituted arylxe2x80x9d denotes an aromatic radical as defined above that is substituted with one or more residues selected from alkyl, substituted alkyl, hydroxyl, cycloalkyl, amino, mono-substituted amino, di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic ring, substituted heterocyclic ring. The term xe2x80x9cheteroarylxe2x80x9d denotes an aryl residue wherein at least one carbon of the aromatic ring radical is replaced with a heteroatom such as oxygen, nitrogen, sulfur, or the like.
The term xe2x80x9calkoxyxe2x80x9d as used herein intends an alkyl group bound through a single, terminal ether linkage; that is, an xe2x80x9calkoxyxe2x80x9d group may be defined as xe2x80x94OR where R is alkyl as defined above. A xe2x80x9clower alkoxyxe2x80x9d group intends an alkoxy group containing from one to six, more preferably from one to four, carbon atoms.
The term xe2x80x9calkylenexe2x80x9d as used herein refers to a difunctional saturated branched or unbranched hydrocarbon chain containing from 1 to 24 carbon atoms, and includes, for example, methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94), propylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94), 2-methylpropylene [xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94], hexylene [xe2x80x94(CH2)6xe2x80x94] and the like. xe2x80x9cLower alkylenexe2x80x9d refers to an alkylene group of from 1 to 6, more preferably from 1 to 4, carbon atoms. The term xe2x80x9ccycloalkylenexe2x80x9d as used herein refers to a cyclic alkylene group, typically a 5- or 6-membered ring.
The terms xe2x80x9calkenexe2x80x9d or xe2x80x9colefinxe2x80x9d as used herein intends a mono-unsaturated or di-unsaturated hydrocarbon group of 4 to 24 carbon atoms. Preferred groups within this class contain 4 to 18 carbon atoms. Asymmetric structures such as (AB)Cxe2x95x90C(CD) are intended to include both the E and Z isomers. This may be presumed in structural formulae herein wherein an asymmetric alkene is present, or it may be explicitly indicated by the bond symbolxe2x80x94.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, the phrase xe2x80x9coptionally substituted lower alkylxe2x80x9d means that the lower alkyl group may or may not be substituted and that the description includes both unsubstituted lower alkyl and lower alkyl where there is substitution.
By the term xe2x80x9ceffective amountxe2x80x9d of a compound or property as provided herein is meant such amount as is capable of performing the function of the compound or property for which an effective amount is expressed. As will be pointed out below, the exact amount required will vary from process to process, depending on recognized variables such as the compounds employed and the processing conditions observed. Thus, it is not possible to specify an exact xe2x80x9ceffective amount.xe2x80x9d However, an appropriate effective amount may be determined by one of ordinary skill in the art using only routine experimentation.
For the purposes of this disclosure, the word xe2x80x9cpyrrolexe2x80x9d may intend either the parent compound (C4H5N), or it may intend the genus of substituted compounds having pyrrole rings that are not part of a larger polycyclic aromatic fused ring systems.
In one aspect, the instant invention provides a process for making a 4-alkyl substituted pyrrole-2-carbaldehyde compound comprising reacting:
a. a pyrrole-2-carbaldehyde compound; and
b. an alkylating agent having at least four carbon atoms; in the presence of at least one catalyst; to form a 4-alkyl substituted pyrrole-2-carbaldehyde compound.
These processes for reacting pyrrole-2-carbaldehyde compounds with alkylating agents are, for the purposes of this disclosure, generally termed xe2x80x9calkylation reactions.xe2x80x9d
The pyrrole-2-carbaldehyde compounds have the general formula: 
A single pyrrole-2-carbaldehyde compound may be employed as a starting material, or mixtures of two or more pyrrole-2-carbaldehyde compounds may also be employed. Generally, the substituent groups (S1, S3, and S5) may be hydrogen, or any organic or inorganic substituent group which results in a reasonably chemically stable pyrrole-2-carbaldehyde compound. Examples of xe2x80x9cSxe2x80x9d groups bonded to the pyrrole ring via inorganic atoms include but are not limited to halogens such as flourine, chlorine, bromine, iodine, and groups derived therefrom; oxygen-containing residues such as hydroxy groups, alkoxy groups, carboxylate groups, and the like; sulfur containing groups such as thiols, thio-ethers, sulfates, sulfonates, and the like, nitrogen containing groups such as amino, nitro or nitroso groups. Preferably, the S3 and/or S5 substituent groups comprise xe2x80x9cRxxe2x80x9d groups comprising hydrogen or carbon-containing groups; i.e., R3 and/or R5 groups. Carbon-containing R3, and/or R5 groups typically have from about 1 to about 18 carbon atoms. More preferably, the R3 and/or R5 substituent groups comprise from about 1 to about 12 carbon atoms. Preferably, the S1, S3, and/or S5, groups, and/or R1, R3, and/or R5 groups are not chemically bonded to each other, to form part of larger polycyclic ring systems.
The S1 group bound to the nitrogen atom may comprise hydrogen, or a variety of organic or inorganic subsubstituent groups which form reasonably chemically stable bonds to the nitrogen atom of the pyrrole ring. In some embodiments, the S1 substituent group may be an xe2x80x9cN-protecting groupxe2x80x9d for the nitrogen atom. N-protecting groups are typically a group which is temporarily and/or removably bonded to the nitrogen atom, and which is present during the alkylation reactions, but then is subsequently removed from the nitrogen by chemical and/or physical methods, and replaced by hydrogen. Typical examples of N-protecting groups include alky or aryl sulfonyl groups, t-butoxycarbonyl groups, or any of the other N-protecting groups known to those skilled in the chemical arts. Because the introduction and removal of N-protecting groups typically adds chemical steps to the methods of the invention, and because such groups typically have an electron-withdrawing effect on the nitrogen atom and the pyrrole-2-carbaldehyde ring, which typically lowers and/alters reaction rates and selectivities, the use of N-protecting groups is within the scope of the invention, but are not generally favored embodiments.
Correspondingly, the 4-substituted pyrrole-2-carbaldehyde product compound or compounds produced by the processes of the invention have the structure: 
wherein R4 is a carbon-containing group introduced by the alkylation reactions of the invention having four or more carbon atoms.
For example, can R4 comprise a substituted or unsubstituted tertiary alkyl residue. Suitable tertiary alkyl R4 residues include those having the structure: 
wherein Rx, Ry, and Rz are the same or different, and comprise at least one carbon atom. Preferably, Rx, Ry, and Rz comprise alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl residues.
R4 groups comprise an organic residue, but the organic residue may additionally contain any organic or inorganic substituent residue or group which results in a reasonably chemically stable pyrrole-2-carbaldehyde compound. R4 may contain aromatic or heteroaromatic residues, although the aromatic or heteroaromatic residues need not be directly bonded to the pyrrole ring. Preferred R4 substituent groups include branched or unbranched, substituted or unsubstituted aliphatic or olefinic residues. Preferably, the R4 substituent group comprises from about 4 to about 18 carbon atoms. More preferably, the R4 substituent group comprises from about 4 to about 12 carbon atoms. Tertiary butyl groups, [xe2x80x94Cxe2x80x94(CH3)3], (which may be alternatively termed xe2x80x9ctert-butylxe2x80x9d or xe2x80x9ct-butylxe2x80x9d groups), are the most preferred R4 groups.
The pyrrole-2-carbaldehyde compounds used as reactants in the practice of the processes of the invention include: 
Preferably, the R3 and/or R5 residues independently comprise hydrogen, a halogen, an alkyl, an aromatic, or a heteroaromatic residue. Preferably, R3 and/or R5 comprise residues having from about 1 to about 25 carbon atoms. More preferably, R3 and/or R5 comprise residues having from about 2 to about 12 carbon atoms. Preferably, the R3 and/or R5 residues are not chemically reactive under the conditions of the subsequent acylation and/or alkylation reactions.
In certain embodiments of the invention, the pyrrole-2-carbaldehyde compound is reacted with an alkylating agent, in the course of an alkylation reaction to selectively form a 4-substituted pyrrole-2-carbaldehyde compound, which comprises 
In many of these embodiments, R3 R4,and/or R5 have the above-described structures. In preferred embodiments, R4 comprises an alkyl, an alkylene, an olefinic, an aromatic, or a heteroaromatic residue. More preferably, the carbon atom of the R4 group bonded to the pyrrole ring is an aliphatic carbon atom (as opposed to a carbon atom which is part of an unsaturated group or residue). R4 groups comprising tertiary alkyl groups or residues are especially preferred in embodiments of the invention comprising alkylation reactions, and tertiary butyl groups are very highly preferred R4 groups.
In one preferred embodiment of the invention, the pyrrole-2-carbaldehyde compound is 
and the 4-substituted pyrrole-2-carbaldehyde compound formed therefrom is 
The processes of the invention employ at least one alkylating agent, which is the ultimate source of the substitutents at the 4-position, such as the R4 residues. Suitable alkylating agents have a carbon-containing residue which is reactive in alkylation reactions, and have at least the number of carbon atoms described above for the R4 substituent. The alkylation reactions of the invention frequently employ acidic catalysts, which typically react with the alkylating agent and/or the pyrrole-2-carbaldehydes, to generate small quantities of high energy intermediates, which produce the alkylated pyrrole-2-carbaldehyde compounds. Those of skill in the art are aware that the high energy intermediates involved are believed to be or be related to xe2x80x9ccarbonium ionxe2x80x9d intermediates. Many alternative methods of generating such high energy xe2x80x9ccarbonium ionxe2x80x9d intermediates both in the presence and absence of catalysts are known to those of skill in the art, and are within the scope of the present invention.
Typical classes of alkylating agents have a substituent which can be reacted to form the high energy carbonium ion intermediates. Typical classes of alkylating agents include an alkyl halide residue, an alcohol residue, or an olefin residue. Alkylating agents having alcohol residues may be employed with either Bronstead acid, or Lewis acid catalysts, and include alkylating agents in which the alcohol residue has been converted to a better xe2x80x9cleaving groupxe2x80x9d by reaction with another chemical group, such as a carboxylic acid or sulfonate group. Preferred alkylating agents having an alcohol residue are tertiary butanol, tertiary butyl acetate, or methyl-tertiary butyl ether. Alkylating agents having an olefin residue, such as ethylene, propylene, 1-butene, cis or trans 2-butene, 1-hexene, and the like, may also be employed with either Bronstead acid, or a Lewis acid catalyst. A preferred alkylating agent having an olefin residue is isobutylene.
Alkylating agents comprising an alkyl halide residue are preferred, especially for alkylation reactions employing aluminum halide catalysts. The halide atoms of the alkyl halide residues include flourine, chlorine, bromine, and iodine. Suitable alkylating agents having an alkyl halide residue include, tertiary butyl chloride, tertiary butyl bromide, and tertiary butyl iodide. Alkylating agents having alkyl halide residues with more than four carbon atoms are suitable for the invention and include compounds such as 2-chloro-2-methylbutane, 1-bromo-1-methyl-1-phenylethane, 1,1,-dimethyl and the like. Those of skill in the art are aware that higher alkyl halides and the carbonium ion intermediates generated from them often undergo rearrangement reactions during the course of the alkylation reaction which can cause xe2x80x9cmigrationxe2x80x9d of organic groups such as methyl groups and aryl groups. For example, 2-chlorobutane may rearrange by the migration of a methyl group to yield a pyrrole product having predominantly tertiary butyl residues. Alkylating agents comprising an alkyl chloride residue are often less reactive than the analogous bromide or iodide compounds, but are sometimes preferred because alkyl chlorides are typically more available and/or less expensive than fluorides, bromides, or iodides. Tertiary butyl chloride is a very highly preferred alkylating agent.
It should be emphasized that the alkylating agent used in the above processes, which introduces a 4-alkyl substituent, need not be a t-butyl group. The alkylation agent may preferably be used to introduce a variety of branched or unbranched, or substituted or unsubstituted alkyl substituents, such as a 4-methyl, or a 4-ethyl substituent, onto the pyrrole, then the 4-alkylsubstituted-pyrrole-2-carbaldehyde could be further elaborated by a wide variety of subsequent chemical reactions, including t-butylation.
The processes of the invention employ catalysts for the alkylation reaction, which typically modify and/or activate the pyrrole and alkylating agents, and modify and/or control the rate and/ or selectivity of the alkylation reaction. The catalysts typically comprise xe2x80x9cacidicxe2x80x9d catalysts, which comprise Bronstead acid catalysts, Lewis acid catalysts, or mixtures thereof.
Bronstead acid catalysts are compounds which function by donating H+ions to the substrates, or to the surrounding medium, which may or may not contain water. Bronstead acid catalysts are particularly suitable when alcohol or olefin alkylating agents are employed in the invention. Examples of Bronstead acid catalysts include but are not limited to mineral acids such as HF, HCl, HBr, HI, H2SO4, HNO3, H3PO4, HBF4 and the like, and strong xe2x80x9corganicxe2x80x9d acids such as methyl sulfonic acid, phenylsulfonic acid, toluenesulfonic acid, trifluoromethylsulfonic acid, sulfonated organic polymers or resins, and the like.
Lewis acid catalysts are preferred catalysts for the alkylation reactions of the invention, and generally comprise compounds having a reactive site or empty orbital which can accept electrons from a Lewis base compound. Well-known classes of compounds which function as Lewis acid catalysts include but are not limited to aluminum compounds, boron compounds, gallium compounds, antimony compounds, zinc compounds, zirconium compounds, tin compounds, solid inorganic acids, or a mixture thereof. Examples of known Lewis acid species include AlBr3, AlCl3, GaCl3, FeCl3, SbCl5, ZnCl2, ZrCl4, SnCl4, BCl3, BF3, SbCl3, alumina, silica, or a mixture thereof. Aluminum trichloride, AlCl3, is a very highly preferred Lewis acid catalyst.
The quantity of catalyst utilized in the alkylation processes of the invention vary widely with the nature of the pyrrole-2-carbaldehyde substrate, the alkylating agent, the solvent, the temperature, the desired reaction rate and selectivity, and other variables. Although xe2x80x9ccatalystsxe2x80x9d are often employed in a molar amount that is less than the amount of substrate, in the processes of the instant invention, the molar quantity of xe2x80x9ccatalystxe2x80x9d used may exceed the molar quantity of the reaction substates. Generally, the catalyst may be present in an amount from about 0.1 to about 5.0 moles per mole of pyrrole-2-carbaldehyde compound. Preferably, the catalyst is present in an amount from about 0.5 to about 3.0 moles per mole of pyrrole-2-carbaldehyde compound.
In alkylations of pyrrole-2-carbaldehyde compounds, it is sometimes observed that about one molar equivalent of catalyst initially complexes with the pyrrole-2-carbaldehyde compound, then a slight excess of catalyst over and above the first molar equivalent is needed to increase reaction rates to a desirable level. Therefore, in more preferred embodiments of the invention, the catalyst is present in an amount from about 1.0 to about 1.5 moles per mole of pyrrole-2-carbaldehyde compound. Even more preferably, the catalyst is present in an amount from about 1.01 to about 1.3 moles per mole of pyrrole-2-carbaldehyde compound.
The alkylation reactions of the processes of the invention need not, but often do occur in the presence of a solvent, or a mixture of solvents. Generally, the solvent is somewhat polar, so as to simultaneously dissolve polar acid catalysts and the organic substrates, while not being so polar or basic that the acid catalysts are effectively neutralized. Therefore, highly basic solvents such as amines are not preferred solvents. Preferably, the solvent is not decomposed by reaction with the catalyst or pyrrole-2-carbaldehyde compound. Therefore, solvents such as alcohols, many of which can react to form ethers in the presence of acids, are not typically preferred solvents. A preferred class of solvents include C1-C2 halogenated organic compounds or liquids. Examples of highly preferred solvent species are 1,2-dichloroethane or methylene chloride, or carbon disulfide.
The alkylation reactions of the invention occur over a broad range of temperatures, depending on the exact structures and concentrations of the pyrrole-2-carbaldehyde compounds, the alkylating agent, the catalyst, the solvent, the desired reaction rates and/or times, and various other factors. Generally, the temperature should be sufficiently high to produce completion of the alkylation reaction within about 48 hours, and low enough to avoid excessive self-condensation reactions of the pyrrole-2-carbaldehyde compounds, which are known to occur at elevated temperatures. Preferably, the alkylation reaction occurs at a temperature from about xe2x88x9220xc2x0 C. to about 60xc2x0 C. More preferably, the reaction occurs at a temperature from about xe2x88x925xc2x0 C. to about 30xc2x0 C. Preferably, the reaction occurs within a time period from about 1 second to about 10 hours. More preferably, the reaction occurs in a time period from about 1 minute to about 5 hours. Most preferably, the reaction can occur in a time period from about 5 minutes to about 2 hours.
Isolation of the reaction product 4-substituted-pyrrole 2-carbaldehyde compounds are typically carried out by standard methods known to those of skill in the art. It is generally necessary to remove, recycle, neutralize, and/or decompose any acid catalysts utilized in the alkylation reaction. Neutralization and/or decomposition of the acid catalysts is typically accomplished by addition of water, hydroxylic compounds, or mineral or organic bases, and is generally accompanied by significantly exothermic reactions and/or liberation of heat. Therefore, the reaction vessel or apparatus is preferably adapted with mixing and/or heat transfer apparatus, so as to minimize local high temperatures during the alkylation reactions or isolation of the products, which can cause side reactions of the product aldehydes. Isolation of the product compounds is typically accomplished by standard means, such as extraction, distillation, crystallization, etc. Preferably, the 4-substituted-pyrrole 2-carbaldehyde compound is isolated by hydrolysis and extraction.
Optionally, the alkyl pyrrole-2-carbaldehydes produced by the processes of the invention (comprising various isomers and substitution patterns) may be hydrogenated, reduced with borohydride or aluminum hydride reagents, or otherwise reduced, to form variously substituted alkyl 2-hydroxymethyl pyrrole compounds. For example: 
The variously substituted pyrrole-2-carbaldehyde utilized in processes of the invention as starting materials can be prepared by any of the methods known to those of skill in the art. Those methods may vary, depending on the desired pattern of substituents at the 1-, 3-, and 5-positions of the pyrrole-2-carbaldehyde. For example, as described above, Mueller-Westerhoff and Sweigers prepared 5-t-butyl-pyrrole-2-carbaldehyde by reacting pyrrole with a Vilsmeir reagent, then alkylating the iminium salt intermediate with t-butyl chloride and aluminum chloride. Reaction of pyrroles with Vilsmeier reagents is a preferred method of synthesizing many 3- or 5-substitued pyrrole-2-carbaldehyde compounds. A preferred method of preparing pyrrole-2-carbaldehyde (the parent compound, C5H5ON) comprises reacting pyrrole (C4H5N) with a Vilsmeir reagent.
Vilsmeir reagents are generally prepared by reacting an N,N-dialkylamide (such as dimethylformamide) and a condensation and/or dehydration reagent. While a variety of condensation and/or dehydration reagents suitable for the preparation of Vilsmeir reagents are known in the art, oxalyl chloride, POCl3, or phosgene are preferred condensation reagents. Hence, in a preferred embodiment of the instant process, the pyrrole-2-carbaldehydes are prepared by reacting pyrrole with an N,N-dialkylformamide and a condensation reagent.
In one aspect, the invention provides a two-step method for making a 4-tertiary-alkyl substituted pyrrole-2-carbaldehyde compound comprising:
a. reacting a pyrrole and a Vilsmeir reagent to produce a 2-substituted pyrrole compound; and
b. further reacting the 2-substituted pyrrole compound with an alkylating agent, in the presence of a catalyst; to form the 4-tertiary-alkyl substituted pyrrole-2-carbaldehyde compound.
In general, the starting pyrrole of this two-step process may have any of the S or R substitutents described herein-above at it""s 1-, 3-, or 5-positions, but it must have hydrogen at it""s 2- or 4-positions. It should be noted that the alkylating agent used in the above process, which results in 4-substituent need not be a t-butyl group. The alkylation agent of this two-step process may preferably be used to introduce a variety of alkyl substituents, including a 4-methyl, or a 4-ethyl substituent onto the pyrrole, then the 4-methyl-pyrrole-2-carbaldehyde or the 4-ethyl-pyrrole-2-carbaldehydes could be further elaborated by a wide variety of subsequent chemical reactions, including t-butylation.
An example of a two step process is shown by the following chemical equation: 
In certain embodiments of the two-step process, the further reacting occurs without isolation of the 2-substituted pyrrole compound, which is an intermediate in the two-step process. In preferred embodiments, the unisolated intermediate 2-substituted pyrrole compound comprises 
It is to be understood that the cationic iminium compound illustrated above is typically the first-formed product of a Vilsmeir reaction, but that the cationic iminium compound might be hydrolyzed to form the illustrated pyrrole-2-carbaldehyde, without actual isolation of either compound, prior to further reacting with an alkylating agent.
Preferably, the R3 and/or R5 substituents of the unisolated intermediates illustrated above may independently comprise hydrogen, an alkyl, an aromatic, a heteroaromatic, an alkoxy, a thio, a carboxyllic acid or ester, an acyl, an amino, a nitro, or a halogen residue; and the R6 and/or R7 substituents of the cationic iminium compound may independently comprise an alkyl, an alkylene, an aromatic, or a heterocyclic residue.
In another aspect, the instant invention provides a process for making 4-t-butyl-pyrrole-2-carbaldehyde, comprising:
a. dispersing pyrrole-2-carbaldehyde and from about 1.0 to about 1.5 molar equivalents of AlCl3 in a solvent:
b. adding from about 0.8 to about 1.3 molar equivalents of t-butyl-chloride to the dispersion, and
c. reacting the dispersion at a suitable temperature and for a time sufficient to form 4-t-butyl-pyrrole-2-carbaldehyde.
Optionally, a 4-t-butyl-pyrrole-2-carbaldehyde produced by this preferred process may be hydrogenated, reduced with borohydride or aluminum hydride reagents, or otherwise reduced, to form 4-t-butyl-2-hydroxymethyl pyrrole.
In yet another aspect, the invention provides the products produced by the process of the invention. In particular, the invention provides 4-t-butyl-2-hydroxymethyl pyrrole produced by the processes of the invention.